Objective: Over 15 years have passed since an enamel matrix derivative (EMD) was introduced as a biologic agent capable of periodontal regeneration. Histologic and controlled clinical studies have provided evidence for periodontal regeneration and substantial clinical improvements following its use. The purpose of this review article was to perform a systematic review comparing the eff ect of EMD when used alone or in combination with various types of bone grafting material. Data Sources: A literature search was conducted on several medical databases including Medline, EMBASE, LILACS, and CENTRAL. For study inclusion, all studies that used EMD in combination with a bone graft were included. In the initial search, a total of 820 articles were found, 71 of which were selected for this review article. Studies were divided into in vitro, in vivo, and clinical studies. The clinical studies were subdivided into four subgroups to determine the eff ect of EMD in combination with autogenous bone, allografts, xenografts, and alloplasts. Results: The analysis from the present study demonstrates that while EMD in combination with certain bone grafts is able to improve the regeneration of periodontal intrabony and furcation defects, direct evidence supporting the combination approach is still missing. Conclusion: Further controlled clinical trials are required to explain the large variability that exists amongst the conducted studies. Keywords: animals, bone grafts, Emdogain, enamel matrix derivative, intrabony periodontal defects, osteoinduction, preclinical studies, systematic review